Parkinson's disease (PD) is a common neurodegenerative disease where the causes of the disease are unknown for ~90% of cases. However, a variety of genetic mutations cause PD in ~10% cases. Among the genetic causes of PD, autosomal dominant forms of familial PD (FPD) share many of the pathological and clinical features with more common late onset sporadic PD. Recently, mutations in LRRK2 gene were shown to cause late-onset FPD with variable penetrance and a-synuclein (a-Syn) pathology (a-synucleinopathy). Thus, PD caused by LRRK2 may involve interactions with environmental and genetic factors. To understand the pathogenic involvement of LRRK2 in causing PD with a-synucleinopathy, we have generated conditional human LRRK2 (hLRRK2) transgenic (Tg) mouse model where high-levels of mutant (R1441C and G2019S) and wild type (WT) hLRRK2 expression can be achieved in subcortical regions. We will determine that when expressed in subcortical neurons, mutant hLRRK2 causes progressive neuropathology in mice, including the loss of dopaminergic neurons. Because only ~50% of mutant hLRRK2 carriers develop PD within 70 years of age, mutant hLRRK2 may combine with other factors to fully express the pathogenic potential. We will test this hypothesis by testing whether mutant hLRRK2 increases vulnerability in dopaminergic neurons to dopaminergic toxin. Further, we will determine whether there is a pathologic interaction between mutant hLRRK2 and a-Syn in causing neurodegeneration of PD relevant neuronal populations.